Continuous Preparation and Use of Dibromoformaldoxime as a Reactive Intermediate for the Synthesis of 3-Bromoisoxazolines

Article abstract of DOI:10.1021/acs.oprd.7b00229

We report the multistep continuous process for the preparation of dibromoformaldoxime (DBFO) as a precursor to generate 3-bromoisoxazolines. We also report process improvements that afford a productivity of over 620 mmol h^-1 of DBFO.

Full text of DOI:10.1021/acs.oprd.7b00229

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Full Paper
Continuous preparation and use of dibromoformaldoxime as a
reactive intermediate for the synthesis of 3-bromoisoxazolines
Claudio Battilocchio, Francesco Bosica, Sam M. Rowe, Bruna Lacerda
Abreu, Edouard Godineau, Matthias Lehmann, and Steven V Ley
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00229 • Publication Date (Web): 03 Aug 2017
Downloaded from http://pubs.acs.org on August 3, 2017
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Continuous preparation and use of dibromoformaldoxime
as a reactive intermediate for the synthesis of 3ꢀ
bromoisoxazolines
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*
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Claudio Battilocchio, Francesco Bosica, Sam M. Rowe, Bruna L. Abreu, Edouard
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Godineau, Matthias Lehmann, Steven V. Ley
1
Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield
2
Road, CB2 1EW, UK; Syngenta Crop Protection AG, Crop Protection Research, Schaffhauser
strasse 101, CHꢀ4332, Switzerland
KEYWORDS. Continuous Processing, Dibromoformaldoxime, Flow Chemistry, Hazardous
Chemistry, Isoxazolines, Multistep synthesis.
ABSTRACT. We report the multistep continuous process for the preparation of
dibromoformaldoxime (DBFO) as a precursor to generate bromoisoxazolines. We also report
ꢀ1
process improvements that afford a productivity of over 620 mmol h of DBFO.
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Dihaloformaldoximes 1 and 2 are highly versatile and reactive intermediates that can be used to
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prepare interesting building blocks (Figure 1). Both dichloro (1) and dibromoformaldoximes (2)
are known to afford, respectively, nitrile oxides (3) and (4) in good yields, via HCl and HBr
elimination. These reactive nitrile oxide species (3 and 4) have been successfully employed in
[3+2] cycloadditions, with a variety of olefins, to yield 3ꢀCl/3ꢀBr substituted isoxazoline
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building blocks (Figure 1). Notably, both 1 and 2 have been commonly used for the preparation
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of microbicides, pesticides or pharmaceutical agents , as well as bioactive natural products such
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as Acivicin (5a) and its unnatural analogue, bromoꢀAcivicin (5b).
Figure 1. a) Synthesis of ClCNO (3) and BrCNO (4), and b) structure of Acivicin and Bromoꢀ
Acivicin.
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Dichloroformaldoxime 1 was originally classified as a warfare agent, as evidenced by its
historical name of phosgene oxime, underlying the toxicity and its selfꢀevident safety issues.
Although less information is known regarding DBFO 2, a similar unfavorable toxicological
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profile can be expected. Moreover, DBFO 2 displays safety properties which make its production
and use on a large scale quite challenging (vide infra).
As part of a synthetic exploratory program to obtain these useful building blocks, we became
interested in the preparation and use of larger amounts of DBFO 2. We argued that the
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preparation of 2 using continuous flow chemistryꢀbased technologies would mitigate the safety
concerns that arise during the handling of this reactive intermediate, especially on scale. A fully
integrated multistep generation and use of DBFO 2 was therefore designed, which addresses the
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challenges associated with molecules of this general type. Here, we disclose our effort towards
the development of a scalable, robust, and controllable generation of 2. In this work, we
demonstrate the clear advantages that accrue from the use of continuous flow chemistry,
enabling the use of this hazardous reagent.
The synthesis of DBFO 2 is known and is outlined in Scheme 1. Previous work reports the use of
glyoxylic acid that is initially condensed with hydroxylamine to afford the intermediate
hydroxyimino acetic acid 6. DBFO 2 is then generated by electrophilic dibromination using
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NBS or bromine
(Scheme 1). Based on handling issues associated with both 6 and 2, we
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have selected a continuous flow approach as an attractive alternative to these batch methods.
While the literature adequately describes the potential hazards associated with DBFO (2, vide
supra), we wished to further use this material as a precursor to 3ꢀbromoisoxazoline building
blocks on a larger scale. Our route, therefore, focused firstly on a stepwise approach which could
subsequently be developed as an integrated, fully telescoped sequence, to obviate the isolation of
highly energetic intermediates 6 and 2 (vide supra).
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Scheme 1. Synthesis of DBFO and cycloaddition to 3ꢀbromoisoxazolines.
Step 1: Preparation of hydroxyiminoacetic acid 6
The differential scanning calorimetry (DSC) analysis of hydroxyiminoacetic acid 6 (see ESI)
indicates an exothermic event with an onset temperature at ca. 124 °C, suggesting that an
autocatalytic decomposition pathway might occur. The associated heat flow to this event is ca.
ꢀ
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2220 J·g , which is problematic. From these data, it appears clearly that only a highly rigorous
control of the temperature could enable safe handling of 6 in batch mode operations.
Although the preparation of 6 under standard batch mode conditions has been performed
previously without incidents, the safety concerns prompted us to explore a continuous process to
this intermediate. We designed a simple flow setꢀup whereby an aqueous stream of glyoxylic
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acid (5 M in H O, 3 mL min ) was combined through a Tꢀpiece with a stream of hydroxylamine
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aqueous solution (5 M in H O, 3 mL min ). The resulting reaction stream was then directed
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towards a 10mL PTFE coiled reactor, operating at room temperature to ensure full conversion to
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hydroxyiminoacetic acid 6. A rapid temperature rise at the Tꢀpiece was immediately observed,
confirming the highly exothermic nature of the process. By using an IR thermalꢀimaging
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camera, we could accurately monitor and interpret these temperature effects. Analysis of the
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reaction showed a noticeable rise in temperature to 30 C at the mixing point. This information
would suggest a batch process producing 6 on scale would require careful mitigation of this
potential hazard by using internal heat exchangers, for example. Under the optimized flow
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conditions, we could safely generate intermediate 6 with a productivity approaching 900 mmol h
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Scheme 2. Reaction flow setup to produce glyoxylic acid oxime 6.
Step 2: synthesis of DBFO 2 from hydroxyiminoacetic acid 6
To understand the safety window associated with the generation/handling of DBFO 2, we
commenced a more detailed study of this intermediate. DSC data (see ESI) indicates a relevant
exothermic event corresponding to an extremely sharp peak, with an onset temperature of 122 °C
ꢀ
and a maximum peak at 131 °C (peak height 66.5 mW). The associated heat output (ca. 950 J·g
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) and further exothermic activity observed above 156 °C are cause for concern. The magnitude
of the sharp exotherm is sufficient to result in a temperature rise under low heat loss conditions
of more than 550K. Due to the structure of 2, it is to be expected the decomposition to also be
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accompanied by the generation of significant quantities of gas. RADEX studies confirmed this
hypothesis, and a pressure rise, attributed to a gas efflux event, was observed from 78 °C up to
ca. 123ꢀ131 °C. The two pressure spikes observed were extremely rapid, indicating the
decomposition of 2 is very likely to be autocatalytic. The potential volume of gas generated was
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estimated to be approximately 57.5 L Kg of 2 (at room temperature). Finally, further thermal
stability tests have confirmed that 2 can undergo violent exothermic decomposition (see ESI).
Although it could be extrapolated from the data that storage of 2 is safe at ꢀ23 °C (at this
temperature, decomposition time is ca. 943h, see ESI), it was decided to dispose of all our stock
of DBFO 2, previously purchased from commercial vendors.
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The major safety concerns discussed above focused our efforts on the development of a
continuous protocol to generate DBFO 2. Prior to this study, the literature suggested the
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conversion of hydroxyiminoacetic acid 6 to 2 was highly pHꢀdependent and that below pH 1.5,
the reaction is very slow. In addition to this, at pH values between 2ꢀ4, the reaction occurs
rapidly, and is dose rate controlled; at pH above 5, the DBFO 2 is generated very rapidly,
however the latter undergoes further HBr elimination to generate nitrile oxide 4, which, in the
absence of an alkene partner, leads to byꢀproduct formation.
The DBFO 2 formation (Step 2) using neat bromine is also described in the literature without the
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need for a base to be present
(76% yield based on Br ). In this case, since 2 eq. of HBr are
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generated during the conversion of 6 to 2, the reaction mixture becomes progressively acidic,
resulting in a decrease of reaction rate. Using a standard batch arrangement, we could identify a
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suitable buffer system to maintain the pH in the target window. Among the many buffer systems
evaluated, NaH PO was optimal (Scheme 3). NaHCO was less effective particularly owing to
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the production of CO gas. Additionally, with the batch process we could not obtain high yields
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of 2 using NaOH as a base.
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Scheme 3. Controlled conversion of 6 to 2 under buffered conditions.
The conversion of 6 to 2 constitutes a particularly exothermic step. During our safety studies
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vide infra), we determined that the decomposition of 2 is indeed highly sensitive to temperature
see ESI). In batch mode, yields of dibromofolmadoxime 2 were scaleꢀdependant, and careful
(
dosage of the bromine was required. We had anticipated therefore that a careful control of the
temperature would improve the reaction reproducibility. Consequently, the use of continuous
flow technology to convert 6 into 2 seemed to be a sensible strategy to achieve accurate control
of both pH and temperature, throughout the reaction profile.
The schematic for the flow system is shown in Table 1 and was based on two pumps, a mixing
element, a pH meter, and a liquidꢀliquid separator.
A piston pump was used to deliver the solution of hydroxyiminoacetic acid 6 (1.7 M solution in
H O), while the solution of Br (2 M in CH Cl ) was introduced via a loaded 50 mL coil (made
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of perfluoroalkoxy alkane, PFA), to avoid a potential corrosion of the pumping units.
We began the optimization program by evaluating a variety of buffers added to the
hydroxyiminoacetic acid 6 flow stream (i.e. solutions of 6 at different pH levels). Different
additives (bases or buffers) were also investigated. Use of NaOH as a base, gave yields of 45% ꢀ
75% (Table 1), which was notably better than the batch process.
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Table 1. Optimization of pH values for the preparation of 2.
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NaOH
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yield
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K HPO4
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K HPO4
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determined by HꢀNMR of crude solution of 2 using 1,3,5ꢀtribromobenzene as internal standard
pH of the aqueous stream feed of 6, see scheme above
b
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Following screening of different buffers, we found that K HPO (1 equiv.) was the optimal
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candidate (pH 5.3), affording 94% yield of DBFO (2), as measured by HꢀNMR (i.e. 1,3,5ꢀ
tribromobenzene as internal standard) (entry 8, Table 1). Mixing, mass (as the reaction is
biphasic) and heat transfer were key aspects for the initial design of our mesofluidic system.
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Mixing. The process involves the mixing of a deep red Br feed in CH Cl solution with a
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colorless aqueous stream of 6 buffered to pH 5.3; simple visual inspection provides qualitative
information regarding the reaction progress (see ESI). Progressive discoloration of the organic
phase along the transparent PFA tube reactor also serves an efficient qualitative way to estimate
conversion of Br . During our early investigations, we noticed that mixing between the two
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phases was inconsistent over an extended period, leading to small variations in yield of DBFO 2.
This lack of robustness was suboptimal and unsuitable for larger scale applications. We therefore
looked at alternative options to upgrade the mixing reproducibility. Our first solution consisted
of a glass column (10 mm i.d. x 100 mm length) packed with glass beads (0.2ꢀ0.5 mm
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diameter).
Here we observed an improvement in mixing and mass transfer between the two
immiscible phases and, using this setꢀup, it was possible to run a series of reproducible
experiments with negligible divergence in yield.
Heat transfer. We again used a thermalꢀimaging camera to generate information regarding the
exothermic behaviour of the reaction (Scheme 4).
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Scheme 4. Optimized synthesis of 2 with the use of thermalꢀimaging camera
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We observed that the yield of 2 roughly correlated with the temperature measured at the mixing
point of the organic feed of Br and aqueous feed of 6. For instance, when the pH of the aqueous
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feed of 6 was around 13 (entry 4, Table 1), the camera indicated a rapid rise in temperature at the
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mixing point to 59.4 C. Under these conditions, 2 was produced in only 45% yield. The reduced
yield clearly confirmed that poor temperature control due to the highly exothermic reaction
rapidly led to decomposition of 2. This trend was indeed confirmed using feeds of 6 set at pH
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.3 and 5.3 (entries 3 and 8, Table 1), where temperatures of 50 °C and 30 °C were detected, and
the yields of DBFO 2, 70 and 94% respectively (Figure 2).
Figure 2. Thermal images of mixing elements using solutions of 6 in H O at pH 13 (left), pH 9.3
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(
middle) and pH 5.3 (right).
This imaging system allowed us to monitor and predict the performance of the reaction based on
temperature during each reaction run. To probe the robustness of the continuous generation of
DBFO 2 as well as confirming the thermalꢀimaging camera as a reliable analytical tool, we
conducted a 4 hrs continuous production run of 2. The reactor setꢀup was fully reproducible over
the timeꢀspan and further confirmed the usefulness of the camera as a potential PAT device.
Finally, although DBFO 2 is known to be soluble in H O, we observed negligible losses of
2
DBFO 2 during the extraction process. We attribute this to the low pH value (~ 1.3) of the
aqueous stream, and a more favorable partition coefficient for the organic layer.
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Step 3: [3+2] cycloaddition with N-vinyl benzamide
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,3,4
The typical batch procedure
for the [3+2] cycloaddition of 4 with an olefin involves its inꢀsitu
generation from DBFO 2 using a weak base. Nevertheless, the controlled generation of bromoꢀ
nitrile oxide 4 from 2 can be a challenging process, especially on scale. This observation is
corroborated by many procedures which use mixing conditions which are heterogeneous, where
for example an insoluble base (i.e. sodium hydrogen carbonate) is stirred with a solution of
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DBFO 2. In addition, studies highlight that the use of organic bases (to adjust the pH values) is
detrimental to the reaction, and therefore this tends to limit the screening to inorganic bases
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only.
To study the various parameters affecting the controlled cycloadditon process, a vinyl amide
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6,17
coupling partner (i.e. Nꢀvinyl benzamide,
8a) was selected as suitable trap for the nitrile
oxide 4. This system also employed a similar approach to the previous step, where biphasic
mixing is a crucial element to the successful outcome of the reaction.
While the use of carbonates, as base, caused issues due to the production of CO gas, it was
2
found that using a phosphate buffer to adjust the pH was an excellent solution. After a thorough
screening of pH conditions, we established that the use of a phosphate buffer at pH 7 represented
the optimized value for the reaction.
1
The stream of DBFO 2 from the previous step (0.94 M, analyzed by HꢀNMR) was mixed with a
ꢀ1
solution of 8a (0.75 M in CH Cl ), with each channel flowing at a rate of 1 mL min , and then
2
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combined with the buffer at a Tꢀpiece. The solution was then reacted in a 5mL reactor coil
residence time 75 seconds), after which the two phases separated with the aid of a liquid/liquid
(
separator. These conditions afforded 7a in 94% yield (Scheme 5).
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Scheme 5. Controlled generation of bromoꢀnitrile oxide and its inꢀsitu trapping with Nꢀvinyl
benzamide.
Analogously to the previous step, to ensure mixing between the two phases a glass column (10
mm id x 100 mm length) packed with glass beads (0.2ꢀ0.5 mm diameter) was employed as static
inꢀline mixer, which resulted in a consistent mass transfer. The use of the thermalꢀimaging
o
camera confirmed that at the set pH value no major rise in temperature was observed (26 C
detected at the mixing point).
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Telescoped protocol and scale up
With a stepwise route to the final 3ꢀbromoisoxazoline 7a in hand, we next focused on the
practicality of using a fully telescoped continuous process. Indeed, such approach would obviate
the isolation and storage of any large amounts of both intermediates 6 and 2.
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An analysis of the essential reaction conditions for each step indicated the need to adjust the
parameters between the steps, most notably pH control and overall throughput.
To connect the first two steps, the pH of the solution of oxime 6 had to be set to a pH value of
5.3. To achieve this, a further integrated step was devised where the solution output from step 1
ꢀ1
was combined with a stream of K HPO (2.5 M solution) at a flow rate of 6.00 mL min
2
4
(Scheme 6). These two solutions were then mixed through a static mixer and directed to a 6 mL
coil, to ensure effective mixing, prior to reaching a multiport valve. After reaching steadyꢀstate,
the solution was directed towards a reservoir for collection. This yielded a solution of oxime 6 at
pH 5.3.
Scheme 6. Modification of step 1, pH adjustment for suitable interface with step 2.
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Moreover, as the throughput of material from step 1 was greater than that one for step 2, further
reaction improvements were necessary.
6
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Given that mass transfer between two immiscible solvents is a crucial parameter, it was
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envisaged that the use of a new “staticꢀmixer coil” would achieve improved and consistent
mixing at high flow rates, hence ensuring a good level of scalability for the synthesis of 2. The
goal was achieved by using a coil preꢀpacked with helical static mixers (20 mL, see ESI).
This arrangement afforded extremely efficient mixing throughout the reactor coil. Using this
ꢀ1
device, it was possible to drive the system to achieve a combined flow rate of 22 mL min . Both
yield and exothermic behaviour were characterized, with consistent outcomes comparable to the
ꢀ1
smallꢀscale procedure. Under the new conditions, a productivity of 10.34 mmol min of
ꢀ1
19
dibromofolmaldoxime 2 (equating to 620.4 mmol h ) was achieved.
To streamline the sequence, we adopted the use of a gravityꢀbased liquid/liquid separator
2
0
(
equipped with a small turbulence settler) which allowed the solution of 2 to be stored
temporarily before directing it towards the following stage of the synthesis (see ESI).
Similarly, we could easily modify step 3 to accommodate a much larger throughput. Both the
dibromofolmaldoxime 2 solution and the vinyl amide partner 8a were pumped at a flow rate of
ꢀ1
ꢀ1
1
0 mL min and then reacted with a solution of phosphate buffer (rate of 20 mL min ) again
ꢀ1
through the static mixer coil, with an overall flow rate of 40 mL min and a residence time of
around 30 s (which represents and improvement compared to the smaller scale reaction). Under
these fully telescoped and optimized conditions, the full system could operate for 2h producing
ꢀ1
ꢀ1
7
a with an output of 117 g h (2.8 kg day ), without issues (Scheme 7).
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Scheme 7. Telescoped system for the synthesis of 7a.
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Library of 3-bromoisoxazolines
With this fully telescoped and high throughput method in place, the sequence could be applied to
the preparation of a small library of 3ꢀbromoꢀisoxazolines. We found that the use of a slightly
larger excess of 2 was needed for most of the styrene derivatives. In these cases, the system was
adjusted to deliver a 0.5 M solution of the styrene coupling partner (Scheme 8).
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Scheme 8. Preparation of a library of 3ꢀbromoisoxazolines 7b-n.
The alkene coupling material (0.5 M in CH Cl ) was loaded onto a loop (5 mL) and combined
2
2
with the DBFO 2 feed (0.94 M in CH Cl ) generated continuously by the telescoped steps 1 and
2
2
2. Both electronꢀrich and electronꢀpoor styrenes performed well and afforded good to excellent
yields of products (e.g. 7f and 7h). Aliphatic alkenes also delivered the expected 3ꢀ
bromoisoxazoline cycloadducts (i.e. 7l), albeit in moderate yield. Ethyl 4,4,4ꢀtrifluoroꢀ2ꢀ
butenoate reacted with inꢀsitu generated nitrile oxide 4 to provide 1:1 mixture of regioisomers
(7m), in good yield. Finally, another particularly interesting example resulted from the use 1,4ꢀ
divinyl benzene which gave bisꢀcycloadduct 7n in quantitative yield.
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Table 2. Library of 3ꢀbromoisoxazolines synthesized using the telescoped protocol.
Conclusions
We have designed and developed a continuous multistep process for the synthesis of DBFO 2
and its continuous use in [3+2] cycloaddition reactions. Dihaloformaldoximes are wellꢀknown
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intermediates, however their synthetic access on scale in batch has proven to be challenging due
to technical and safety issues. We have therefore assembled a fully integrated continuous
process, generating DBFO 2 “on demand”. We believe this process offers several advantages
such as: i) use of benchꢀstable starting material feeds; ii) generation and direct use of highly
energetic intermediates (i.e. hydroxyiminoacetic acid 6 and DBFO 2); iii) improved process
robustness and reliability over the batch mode, on large scale (ca. 100ꢀ500g); iv) high
productivity, using a small footprint system, equating to kg amounts of 3ꢀbromoꢀisoxazoline
products per day. In addition, the scope of the newly formulated process could be expanded to
rapidly prepare a library of 3ꢀbromoisoxazolines intermediates (7bꢀo).
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ASSOCIATED CONTENT
Supporting Information. The following files are available free of charge:Compounds
characterization data (PDF) and reaction setup (PDF); additional data is available from the
University of Cambridge Data Repository website: https://doi.org/10.17863/CAM.12125.
AUTHOR INFORMATION
Corresponding Author
Dr Claudio Battilocchio, email: cb700@cam.ac.uk
Dr. Edouard Godineau, email: edouard.godineau@syngenta.com
ACKNOWLEDGMENTS
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We would like to thank Syngenta Crop Protection AG (CB) and the EPSRC (SVL, grant #
EP/K009494/1, EP/M004120/1 and EP/K039520/1) for financial support. We thank Ian Priestley
and Markus Luginbuehl for the safety discussions on the intermediates mentioned herein. We
thank Myriem El Qacemi and Tomas Smejkal for their fruitful discussions and their support. We
thank Prashantha Kamath for the synthesis of Nꢀvinylbenzamide. We would also like to thank
Duncan Guthrie (Vapourtec Ltd) for his support.
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Sartori, M. The war gases, chemistry and analysis, London: J. & A. Churchill, Ltd., 1939.
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E.I.P.; Berton, J.K.E.T.; Battilocchio, C.; Ley, S.V.; Stevens, C.V. Chem. Soc. Rev., 2016, 45,
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4
Ley, S.V.; Fitzpatrick, D.E.; Myers, R.M.; Battilocchio, C.; Ingham, R.J. Angew. Chem. Int. Ed.
2015, 54, 10122ꢀ10136; d) Brzozowski, M.; O’Brien, M.; Ley, S.V.; Polyzos, A. Acc. Chem.
Res, 2015, 349ꢀ362; e) Hessel, V.; Kralisch, D.; Kockmann, N.; Noël T.; Wang, Q.
ChemSusChem 2013, 6, 746ꢀ789; f) Pastre, J.C.; Browne, D.L.; Ley, S.V. Chem. Soc. Rev. 2013,
42, 8801ꢀ8869; g) Webb, D.; Jamison, T.F. Chem. Sci. 2010, 1, 675ꢀ680; h) Hartman, R.L.;
McMullen J.P.; Jensen, K.F. Angew. Chem. Int. Ed. 2011, 50, 7502ꢀ7519
7
For selected examples from our groups, see: a) Battilocchio, C.; Iannucci, G.; Wang, S.;
Godineau, E.; Kolleth, A.; De Mesmaeker, A.; Ley, S.V. React. Chem. Eng., 2017, 2, 295ꢀ298;
b) Battilocchio, C.; Feist, F.; Hafner, A.; Simon, M.; Tran, D.N.; Allwood, D.M.; Blakemore,
D.C.; Ley, S.V. Nature Chem., 2016, 8, 360ꢀ367; c) Lau, S.ꢀH.; Galván, A.; Merchant, R.R.;
Battilocchio, C.; Souto, J.A.; Berry, M.B.; Ley, S.V. Org. Lett. 2015, 17, 3218ꢀ3221; d)
Battilocchio, C.; Deadman, B.J.; Baxendale, I.R.; Kitching, M.O.; Ley, S.V. Chem. Eur. J. 2013,
19, 7917ꢀ7930; e) Battilocchio, C.; Baxendale, I.R.; Biava, M.; Kitching, M.O.; Ley, S.V. Org.
Process Res. Dev. 2012, 16, 798ꢀ810; f) O'Brien, M.; Taylor, N.; Polyzos, A.; Baxendale, I. R.;
Ley, S. V. Chem. Sci. 2011, 2, 1250ꢀ1257; g) Polyzos, A.; O'Brien, M.; Petersen, T.P.;
Baxendale, I.R.; Ley, S.V. Angew. Chem. Int. Ed., 2011, 1190ꢀ1193; h) O’Brien, M.; Baxendale,
I.R.; Ley, S.V. Org. Lett. 2010, 1596ꢀ1598;
8
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990 ; b) Han, Y.; Yang, S.ꢀM.; Wang, X.ꢀY.; Li, F.ꢀN. Archives of Pharmacal Research 2014,
37, 440ꢀ451
9
a) Soleimani, E.; Yazdani, H.; Saei P. Tet. Lett. 2015, 56, 1635ꢀ1637; b) Rohloff, J. C.;
Robinson III, J.; Gardner J. O. Tet. Lett. 1992, 33, 3113ꢀ3116; d) Orth, R.; Bottcher, T.; Sieber,
S. A. Chem. Comm. 2010, 46, 8475ꢀ8477; e) M. Savion, M. G. Memeo, B. Bovio, G. Grazioso,
L. Legnani, P. Quadrelli, Tetrahedron 2012, 68, 1845ꢀ1852
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a) Schwolow, S.; Hollmann, J.; Schenkel, B.; Röder, T. Org. Proc. Res. & Dev. 2012, 16,
1513ꢀ1522; b) Reckamp, J. M.; Bindels, A., Duffield, S., Liu, Y. C.; Bradford, E.; Ricci, E.;
Susanne, F.; Rutter, A. Org.Proc. Res. & Dev. 2017, ASAP.
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Please visit the FLIR website: http://www.flir.com.hk/cs/display/?id=41965
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Ley, S.V.; Ingham, R.J.; O’Brien, M.; Browne, D.L. Beilstein J. Org. Chem. 2013, 9, 1051ꢀ
1072
1
3
RADEX is commercialized by SYSTAG and is a versatile tool which can be operated in
several modes such as dynamic, isoperibolic and adiabatic. It is used as a dynamic screening
tool, providing data on heatꢀ and pressureꢀgenerating events. For more information, please visit:
https://www.systag.ch/applications/thermalꢀanalysis.html
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a) Naber, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2010, 49, 9469ꢀ9474; b) Bogdan, A.;
McQuade, D. T. Beilstein J. Org. Chem. 2009, 5, No. 17.
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Similar set up using Rashig rings as static mixers: Kilcher, E.; Freymond, S.; Vanoli, E.; Marti,
R.; Schmidt, G.; Abele, S. Org. Proc. Res. & Dev. 2016, 20, 432ꢀ439
16
Nꢀvinylbenzamide 8a was prepared according to: Tu, S.; Zhang, C. Org. Process Res. Dev.
015, 19, 2045ꢀ2049; see also: O'Sullivan, A. C.; El Qacemi, M.; Cassayre, J. Y.; Pitterna, T.;
2
Stoller, A. 2017, WO2017050921; Cassayre, J. Y., Stoller, A.; Pitterna, T.; El Qacemi, M. 2017,
WO2017050922
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Cycloaddition of dibromoformaldoxime 2 with Nꢀvinylbenzamide 8a is described in: Joest, C.;
Nitsche, C.; Scholz, T.; Roux, L.; Klein, C. D. J. Med. Chem. 2014, 57, 7590ꢀ7599.
18
Please visit the Vapourtec website: https://www.vapourtec.com/products/flowꢀreactors/largeꢀ
diameterꢀtubularꢀreactorꢀforꢀrapidꢀmixingꢀfeatures
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Please visit the HiTec Zang website: http://www.hitecꢀzang.de/en/laboratoryꢀdevices/syringeꢀ
doser.html
1
9
Please visit the HiTec Zang website: http://www.hitecꢀzang.de/en/laboratoryꢀdevices/syringeꢀ
doser.html
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Recent examples of liquid/liquid separations under continuous flow: a) O'Brien, M.; Koos, P.;
Browne, D.L.; Ley, S.V. Org. Biomol. Chem. 2012, 7031ꢀ7036; b) Hu, D.X.; O’Brien, M.; Ley,
S.V. Org. Lett. 2012, 4246ꢀ4249; c) O'Brien, M.; Konings, L.; Martin, M.; Heap, J. Tetrahedron.
Lett. 2017, 58, 2409ꢀ2413.
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5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment